Fragment based drug discovery (FBDD) applied to two enzymes of folate biosynthetic pathway from Mycobacterium tuberculosis

• Grant number: 13/15906-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2014
• End date: February 28, 2018
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Marcio Vinicius Bertacine Dias
• Grantee: João Augusto Ribeiro
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 10/15971-3 - Structural characterization of enzymes from antibiotic biosynthetic pathways with biotechnological interest, AP.JP

Abstract

Infectious diseases stand out as public health problem worldwide and represent a major cause of death in the human population, especially in less developed countries. Tuberculosis is still ranked among the three infectious diseases that kill most in the world due to the emergence of drug-resistant strains, the association with HIV and long treatment period. However, there no a solid investment of pharmaceutical companies in the search for new therapies due to the prospect of low financial returns. Thus, the survey of public funds is essential for the development of new drugs and may be held in partnerships with major pharmaceutical companies. For this, a strategy is the development of inhibitors of the infectious agent enzymes or enzymes which are also conserved in humans, but significant differences that may lead to the development of specific molecules. The folate synthesis pathway presents both types of enzymes, and drugs that inhibit its two enzymes have been used for decades to treat several types of infections, and no effective inhibitors for this pathway in the treatment of tuberculosis. In this project, we intend to use the technique fragment based drug discovery (FBDD) to identify relatively simple molecules that can be chemically modified for the generation of potent inhibitors of folate pathway enzymes in Mycobacterium tuberculosis. Thus, a variety of biophysical and crystallographic techniques will be applied in screening and validation of candidate small molecules. The modification or addition of functional groups to fragments identified will be held by research groups in the field of organic synthesis. Thus, proposes to study two enzymes of the pathway, these being the dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFR) in order to assist in the development of new drugs against tuberculosis.

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BERTACINE DIAS, MARCIO V.; SANTOS, JADEMILSON C.; LIBREROS-ZUNIGA, GERARDO A.; RIBEIRO, JOAO A.; CHAVEZ-PACHECO, SAIR M.. Folate biosynthesis pathway: mechanisms and insights into drug design for infectious diseases. Future Medicinal Chemistry, v. 10, n. 8, p. 935-959, APR 2018. (15/09188-8, 13/15906-5, 10/15971-3)

DE OLIVEIRA, GABRIEL S.; ADRIANI, PATRICIA P.; RIBEIRO, JOAO AUGUSTO; MORISSEAU, CHRISTOPHE; HAMMOCK, BRUCE D.; DIAS, MARCIO VINICIUS B.; CHAMBERGO, FELIPE S.. The molecular structure of an epoxide hydrolase from Trichoderma reesei in complex with urea or amide-based inhibitors. International Journal of Biological Macromolecules, v. 129, p. 653-658, MAY 15 2019. (13/15906-5, 16/12859-4, 15/03329-9, 15/09188-8, 18/00351-1, 14/24107-1, 17/25705-8)

KRONENBERGER, THALES; FERREIRA, GLAUCIO MONTEIRO; FERREIRA DE SOUZA, ALFREDO DANILO; SANTOS, SORAYA DA SILVA; POSO, ANTTI; RIBEIRO, JOAO AUGUSTO; TAVARES, MAURICIO TEMOTHEO; PAVAN, FERNANDO ROGERIO; GOULART TROSSINI, GUSTAVO HENRIQUE; BERTACINE DIAS, MARCIO VINICIUS; et al. Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors. Bioorganic & Medicinal Chemistry, v. 28, n. 15, AUG 1 2020. (13/18160-4, 17/00689-0, 13/15906-5, 17/25543-8)

RIBEIRO, JOAO AUGUSTO; CHAVEZ-PACHECO, SAIR MAXIMO; DE OLIVEIRA, GABRIEL STEPHANI; SILVA, CATHARINA DOS SANTOS; PIMENTA GIUDICE, JOAO HENRIQUE; LIBREROS-ZUNIGA, GERARDO ANDRES; BERTACINE DIAS, MARCIO VINICIUS. Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 75, n. 7, p. 682-693, JUL 2019. (13/15906-5, 15/09188-8, 18/00351-1, 14/24486-2, 16/18721-4)

RIBEIRO, JOAO AUGUSTO; CHAVEZ-PACHECO, SAIR MAXIMO; DE OLIVEIRA, GABRIEL STEPHANI; SILVA, CATHARINA DOS SANTOS; PIMENTA GIUDICE, JOAO HENRIQUE; LIBREROS-ZUNIGA, GERARDO ANDRES; BERTACINE DIAS, MARCIO VINICIUS. Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 75, p. 12-pg., 2019-07-01. (13/15906-5, 18/00351-1, 15/09188-8, 14/24486-2, 16/18721-4)

RIBEIRO, JOAO A.; HAMMER, ALEXANDER; LIBREROS-ZUNIGA, GERARDO A.; CHAVEZ-PACHECO, SAIR M.; TYRAKIS, PETROS; DE OLIVEIRA, GABRIEL S.; KIRKMAN, TIMOTHY; EL BAKALI, JAMAL; ROCCO, SILVANA A.; SFORCA, MAURICIO L.; et al. Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis. ACS INFECTIOUS DISEASES, v. 6, n. 8, p. 2192-2201, AUG 14 2020. (10/15971-3, 13/15906-5, 18/00351-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

RIBEIRO, João Augusto. Application of the FBDD technique ¨fragment based drug discovery¨ to the DHFR enzyme of the folate biosynthesis pathway in Mycobacterium tuberculosis. 2018. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.